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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 1 336-340
Copyright © 2006 by The Endocrine Society

BRIEF REPORT

Reactive Oxygen Species-Induced Oxidative Stress in the Development of Insulin Resistance and Hyperandrogenism in Polycystic Ovary Syndrome

Frank González, Neal S. Rote, Judi Minium and John P. Kirwan

Department of Reproductive Biology (F.G., N.S.R., J.M.), Department of Medicine and Schwartz Center for Metabolism and Nutrition (J.P.K.), Case Western Reserve University School of Medicine, Cleveland, Ohio 44109

Address all correspondence and requests for reprints to: Frank González, MetroHealth Medical Center, Department of Obstetrics and Gynecology, Hamann S4-44, 2500 MetroHealth Drive, Cleveland, Ohio 44109. E-mail: fgonzalez{at}metrohealth.org.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Insulin resistance and chronic low level inflammation are often present in women with polycystic ovary syndrome (PCOS).

Objective: The purpose of this study was to determine the effects of hyperglycemia on reactive oxygen species (ROS) generation from mononuclear cells (MNCs) in PCOS.

Design: This was a prospective controlled study.

Setting: The study was conducted at an academic medical center.

Patients: The study population consisted of 16 women with PCOS (eight lean, eight obese) and 15 age- and body composition-matched controls (eight lean, seven obese).

Main Outcome Measures: Insulin sensitivity was derived from a 2-h, 75-g oral glucose tolerance test (ISOGTT). ROS generation and p47phox protein expression were quantitated from MNCs obtained from blood drawn fasting and 2 h after glucose ingestion.

Results: ISOGTT was lower in PCOS, compared with controls (3.1 ± 0.3 vs. 6.3 ± 0.9, P < 0.003). The percent change in ROS generation from MNCs was higher in lean and obese PCOS, compared with lean controls (138.8 ± 21.3 and 154.2 ± 49.1 vs. 0.6 ± 12.7, P < 0.003). The percent change in ROS generation from MNCs correlated positively with glucose area under the curve (r = 0.38, P < 0.05), and plasma levels of testosterone (r = 0.59, P < 0.002) and androstenedione (r = 0.50, P < 0.009). The percent change in p47phox from MNCs was also higher in lean and obese PCOS, compared with lean controls (36.2 ± 18.2 and 39.1 ± 8.0 vs. –13.7 ± 8.7, P < 0.02), and correlated negatively with ISOGTT (r = –0.39, P < 0.05).

Conclusion: ROS generation from MNCs in response to hyperglycemia is increased in PCOS independent of obesity. The resultant oxidative stress may contribute to a proinflammatory state that induces insulin resistance and hyperandrogenism in women with this disorder.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
IN POLYCYSTIC OVARY syndrome (PCOS), stimulation of reactive oxygen species (ROS) generation from mononuclear cells (MNCs) by hyperglycemia may play a role in inflammation through the release of TNF{alpha} from circulating MNCs. The superoxide radical in particular is a ROS that is generated by the activity of membrane-bound nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (1, 2). Formation of a functional NADPH oxidase enzyme complex is dependent on the phosphorylation of cytosolic p47phox, thereby initiating its translocation to the cell membrane (3, 4). The resultant oxidative stress causes increased tissue/cellular damage manifested by lipid peroxidation, protein oxidation and DNA damage (5, 6, 7). This in turn activates nuclear factor-{kappa}B, a proinflammatory transcription factor that promotes the transcription of TNF{alpha}, a known mediator of insulin resistance (1, 8, 9, 10). We have previously reported that in PCOS, circulating TNF{alpha} levels are elevated independent of obesity and that MNC-derived TNF{alpha} release is altered in response to hyperglycemia (11, 12). Thus, ROS generation from MNCs in response to hyperglycemia may serve as an inflammatory trigger for the induction of insulin resistance in PCOS.

We examined ROS generation in MNCs of patients with PCOS before and after hyperglycemia. We measured protein expression of p47phox and plasma thiobarbituric acid-reactive substances (TBARS), a commonly used index of lipid peroxidation. We hypothesized that ROS generation, p47phox expression and TBARS are increased in women with PCOS in response to hyperglycemia, compared with age- and body composition-matched controls.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Sixteen women with PCOS (eight lean and eight obese) between 20 and 33 yr of age and 15 weight-matched control subjects (eight lean and seven obese) between 20 and 39 yr of age volunteered to participate in the study. Subjects in the present report represent part of a larger cohort that are involved in our studies on PCOS and insulin resistance, and some of their data have been presented in a previous publication (12). The women with PCOS and control subjects were selected as previously described using the Rotterdam criteria to make the diagnosis of PCOS (12, 13). All subjects provided written informed consent in accordance with the Case Western Reserve University and MetroHealth Medical Center guidelines for the protection of human subjects.

All subjects ingested a 75-g glucose beverage. Blood samples were drawn at 0 (fasting), 30, 60, 90, and 120 min for glucose and insulin determination. Areas under the curve (AUCs) for glucose were calculated using the trapezoidal rule (14). Insulin sensitivity (IS) was derived from a 2-h, 75-g oral glucose tolerance test (ISOGTT) (15). Dual-energy absorptiometry was used to determine percent total body fat and percent truncal fat (Hologic, Inc., Waltham, MA). Truncal fat content was defined as the area between the dome of the diaphragm (cephalad limit) and the top of the greater trochanter (caudal limit) (16).

MNC isolation and measurement of ROS generation were performed as previously described (17). The protein expression of p47phox and actin was quantitated by Western blotting using a monoclonal antibody against p47phox (Transduction Laboratories, Inc., San Diego, CA) at a dilution of 1:500, or actin (Santa Cruz Biotechnology, Santa Cruz, CA) at a dilution of 1:1000 as previously described (18). Densitometry was performed using 1D Image Analysis software (version 3.6; Kodak, Rochester, NY), and all values for p47phox were corrected for loading using those obtained for actin.

Plasma glucose, insulin, testosterone, androstenedione, dehydroepiandrosterone-sulfate, and C-reactive protein (CRP) were measured as previously described (12). Plasma TBARS was measured by fluorescence (OXItek; ZeptoMetric Corp., Buffalo, NY). All samples were measured in duplicate in the same assay.

Statistics

Data were analyzed using StatView (SAS Institute, Cary, NC). Descriptive and percent change data were compared using an unpaired Student’s t test or ANOVA for multiple group comparisons. Detection of significance by ANOVA was followed by a post hoc analysis. Differences between pre- and postglucose challenge variables within groups were analyzed using the paired Student t test. Correlation analyses were performed by linear regression. All values are expressed as means ± SE. An alpha level of 0.05 was used to determine statistical significance.


   Results
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 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Weight, body mass index (BMI), percent total body fat, and waist circumference were greater (P < 0.03) in obese subjects, compared with those who were lean, whether or not they had PCOS (Table 1Go). Obese subjects also had greater (P < 0.03) percent truncal fat, compared with lean subjects, whether or not they had PCOS.


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  		TABLE 1. Subject characteristics

 
Compared with control subjects, women with PCOS exhibited higher (P < 0.03) circulating levels of testosterone (83.1 ± 7.0 vs. 36.9 ± 3.7 ng/dl), androstenedione (3.6 ± 0.2 vs. 1.7 ± 0.1 ng/ml), and dehydroepiandrosterone-sulfate (270 ± 32 vs. 183 ± 21 µg/dl). Androgen results were similar when subjects were grouped by body mass (data not shown). Fasting plasma concentrations of CRP were higher (P < 0.005) in the obese, whether or not they had PCOS (Table 1Go). Basal plasma TBARS was similar in women with PCOS and control subjects. However, the percent change in plasma TBARS in response to hyperglycemia was higher (P < 0.05) in obese women with PCOS, compared with lean and obese controls.

ISOGTT was lower in women with PCOS, compared with controls (3.1 ± 0.3 vs. 6.3 ± 0.9, P < 0.003). When subjects were grouped by body mass (Table 1Go), ISOGTT was lower (P < 0.05) in obese women with PCOS, compared with either control group. Lean women with PCOS exhibited an ISOGTT that was lower (P < 0.04) than that of lean controls. ISOGTT was negatively correlated with BMI (r = –0.43, P < 0.02), percent body fat (r = –0.41, P < 0.03), percent truncal fat (r = –0.51, P < 0.004), and waist circumference (r = –0.49, P < 0.008) for the combined groups (data not shown).

As depicted in Fig. 1AGo, the percent change in ROS generation from MNCs was higher (P < 0.009) in lean and obese women with PCOS, compared with lean controls. The percent change in p47phox protein expression from MNCs was also higher (P < 0.02) in both groups of women with PCOS, compared with lean controls (Fig. 1Go, B and C).



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  		FIG. 1. A, The percent change in ROS generation from MNCs when fasting samples (pre) were compared with the samples collected 2 h after glucose ingestion (post). *, ROS generation in lean women with PCOS was greater, compared with that of lean controls, P < 0.009. {dagger}, ROS generation in obese women with PCOS was greater, compared with that of lean controls, P < 0.003. B, Representative Western blots from the four study groups showing the change in quantity of p47phox in MNC homogenates when fasting samples (pre) were compared with the samples collected 2 h after glucose ingestion (post). C, Densitometric quantitative analysis of p47phox protein content in MNCs. *, The percent change in p47phox in lean women with PCOS was greater, compared with that of lean controls, P < 0.02. {dagger}, The percent change in p47phox in obese women with PCOS was greater, compared with that of lean controls, P < 0.007.

 
Glucose AUC was positively correlated with the MNC-derived percent change in ROS generation (r = 0.38, P < 0.05) and p47phox protein expression (r = 0.40, P < 0.04) for the combined groups. p47phox expression was also positively correlated with percent truncal fat (r = 0.38, P < 0.05) and negatively correlated with ISOGTT (r = –0.39, P < 0.05) for the combined groups (data not shown).

Plasma levels of testosterone and androstenedione were positively correlated with the percent change in ROS generation from MNCs (r = 0.59, P < 0.002; r = 0.50, P < 0.009) for the combined groups (Fig. 2Go, A and B).



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  		FIG. 2. A, Correlation between plasma testosterone and the percent change in ROS generation from MNCs. B, Correlation between plasma androstenedione and the percent change in ROS generation from MNCs. Due to technical difficulties, these data were derived from 13 control subjects and 14 women with PCOS. {circ}, Control subjects; •, women with PCOS. The percent change in ROS generation from MNCs was determined when fasting samples (pre) were compared with the samples collected 2 h after glucose ingestion (post).

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Our data clearly show that hyperglycemia stimulates ROS generation from MNCs of women with PCOS independent of obesity. There is also increased protein expression of p47phox, the key protein component of NADPH oxidase, in women with PCOS, which is again independent of obesity. Lean women with PCOS demonstrate increased ROS generation and p47phox expression, compared with lean controls, and these increases are similar to obese subjects, whether or not they have PCOS. The protein expression of p47phox is inversely related to insulin sensitivity, and ROS generation is directly related to androgen levels. These findings suggest that ROS-induced oxidative stress may play a role in the development of insulin resistance and hyperandrogenism in PCOS. Furthermore, the association between p47phox protein expression and percent truncal fat suggests that increased abdominal adiposity may be a key determinant of the ROS-induced oxidative stress observed in obese women with PCOS and a potential modulator of insulin action in these individuals.

Negligible induction of oxidative stress may be the normal in vivo response to physiologic hyperglycemia in young, healthy, lean women. Lean controls showed minimal alteration in MNC-derived ROS generation and p47phox protein expression in response to hyperglycemia. Limited induction of NADPH oxidase activity and subsequent ROS generation may be a physiological benefit in the presence of hyperglycemia when there is a need to increase glucose disposal. Increased TNF{alpha} release from MNCs after activation by ROS-induced oxidative stress may inhibit insulin signaling and impair glucose uptake. This is consistent with our previous reports that hyperglycemia suppresses TNF{alpha} release from MNCs in young, healthy, lean men and women (19, 20). Thus, facilitation of glucose disposal in lean controls may be partially due to the control of NADPH oxidase activity to limit ROS generation in the postprandial state, thereby optimizing insulin signaling.

The MNCs of women with PCOS are in a proinflammatory state as evidenced by the increased sensitivity to physiologic hyperglycemia and elevated plasma CRP (21). ROS generation and p47phox protein expression increased in response to the oral glucose challenge in lean women with PCOS, compared with lean controls. Obese women with PCOS also exhibited increases in these parameters, compared with obese and lean controls. The resultant oxidative stress suggested by the increase in TBARS in PCOS, particularly obese PCOS, may help to explain our previous observations that hyperglycemia alters TNF{alpha} release in women with PCOS (12). The stimulatory impact of hyperglycemia on oxidative stress is suggested by the direct relationship between glucose AUC and both ROS generation and p47phox protein expression. Lipid and protein intakes have been shown to elicit similar proinflammatory responses (22). It is possible that in PCOS, feeding results in increased oxidative stress that triggers an acute inflammatory response to promote insulin resistance. This concept is further supported by the inverse correlation between p47phox protein expression and ISOGTT along with previous reports of a reduction in oxidative stress and inflammatory mediators after caloric restriction in the obese and after a 2-d fast in normal subjects (23, 24).

The hyperinsulinemia that occurs after an oral glucose challenge may contribute to ROS-induced oxidative stress. The oxidative effects of insulin have been demonstrated in vitro and in response to both physiological and pharmacological insulin infusions in vivo (25, 26, 27). Most recently, physiological insulin infusion in the obese suppressed ROS generation and nuclear factor-{kappa}B activation (28). This latter finding suggests that insulin exerts an antiinflammatory effect that ameliorates the proinflammatory response to physiological hyperglycemia.

Our data also suggest that in PCOS, there may be a link between abdominal adiposity and oxidative stress. Although not evident in the present study, our group and others (12, 29) have previously shown that aside from obese women with PCOS, abdominal adiposity can be increased in lean women with the disorder. The change in p47phox protein expression from MNCs in response to hyperglycemia was directly related to abdominal adiposity. MNCs are known to migrate into adipose tissue to activate adipocyte TNF{alpha} production (30). It is now clear that the major source of TNF{alpha} in excess adipose tissue is MNC-derived macrophages present in the stromal-vascular compartment (30, 31). Inflamed adipose tissue, especially in the abdominal region, may perpetuate the hyperglycemia-induced oxidative stress to promote altered TNF{alpha} release from MNCs in obese women with PCOS. These findings are consistent with previous observations in young adults demonstrating that changes in insulin sensitivity are a function of abdominal adiposity (32). Thus, the increased p47phox expression and subsequent ROS generation may, in turn, promote the insulin resistance observed in obese women with PCOS.

In PCOS, oxidative stress in response to hyperglycemia may be capable of directly stimulating hyperandrogenism. This is suggested by the association between plasma testosterone or androstenedione and ROS generation. In vitro studies have shown that the ovarian steroidogenic enzymes responsible for androgen production are stimulated by oxidative stress and inhibited by antioxidants such as statins (33, 34). Androgen-producing theca cells proliferate in vitro in the presence of TNF{alpha} (35). Macrophage infiltration of the ovary has been previously demonstrated (36). Thus, oxidative stress from glucose-activated MNCs recruited into the polycystic ovary may induce a local inflammatory response that stimulates ovarian androgen production in women with PCOS.

In conclusion, women with PCOS exhibit increased MNC-derived ROS generation and p47phox expression in response to physiologic hyperglycemia that is independent of obesity. The resultant oxidative stress induces a proinflammatory state that may contribute to insulin resistance and hyperandrogenism in PCOS. The association between the change in p47phox expression and abdominal fat suggests that increased adiposity is an additional perpetuator of insulin resistance in PCOS.


   Acknowledgments
 
We thank the nursing staff of the General Clinical Research Center for supporting the implementation of the study and assisting with data collection. We also thank Blathnaid Ward for technical assistance and Christine Marchetti for assistance with the graphics preparation.


   Footnotes
 
This work was supported by National Institutes of Health Grants HD-01273 (Women’s Reproductive Health Research Program) to the Department of Obstetrics and Gynecology at MetroHealth Medical Center and MO1 RR-080 to the General Clinical Research Center.

The authors have no conflict of interest.

First Published Online October 25, 2005

Abbreviations: AUC, Area under the curve; BMI, body mass index; CRP, C-reactive protein; ISOGTT, insulin sensitivity derived from an oral glucose tolerance test; MNC, mononuclear cell; NADPH, nicotinamide adenine dinucleotide phosphate; PCOS, polycystic ovary syndrome; ROS, reactive oxygen species; TBARS, thiobarbituric acid-reactive substances.

Received July 29, 2005.

Accepted October 17, 2005.


   References
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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